AEDs in 2011: A Critical Comparative Review December 3, 2011

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1 AEDs in 2011: A Critical Comparative Review December 3, 2011 Selim R. Benbadis, M.D. University of South Florida Tampa, FL American Epilepsy Society Annual Meeting

2 Disclosure Speakers bureau Consultant Research support Cyberonics X X GSK X X Lundbeck X X X Optima X Pfizer X X Schwarz X Sleepmed X X Sunovion X X UCB X X X XLTEK X American Epilepsy Society Annual Meeting

3 Learning Objectives To review similarities and differences among antiepileptic drugs. To critically discuss factors that differentiate among various medications, and factors that do not. American Epilepsy Society Annual Meeting

4 NEWER DRUGS Felbamate (1993) Gabapentin (1993) Lamotrigine (1994) Topiramate (1997) Tiagabine (1998) Levetiracetam (1999) Oxcarbazepine (2000) Zonisamide (2000) Pregabalin (2005) Rufinamide (2009) Lacosamide (2009) Vigabatrin (2009) Ezogabine (2011) Clobazam (2011) Apples and oranges

5 WHAT TO COMPARE Efficacy Tolerability & adverse events Dosing Titration Drug-drug interactions Use in comorbidities Pregnancy Mechanism of action FDA indications Formulations Cost

6 Best median seizure reduction (adjunct for partial epilepsy) EZG (900mg) 40% [Brodie et al, 2010] GBP (1800mg) 26% [Package insert] LCM (600mg) 40% [Package insert] LEV (3000mg) 39% [Package insert] LTG (500mg) 36% [Package insert] OXC (1200mg) 40% [Package insert] PGB (600mg) 48% [Package insert] TGB (56mg) 36% [Package insert] TPM (800mg) 43% [Package insert] ZNS (400mg) 40% [Package insert]

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8 Methods: Systematic review of randomized trials (RCTs) comparing a new AED as add-on. Primary outcomes: responder ( 50% seizure reduction) and withdrawal (tolerability) rates. Results 62 placebo-controlled (N=12,902 patients) and 8 head-to-head RCTs (N=1,370) Indirect comparisons of responder rate based on relative measurements of treatment effect (ORs) favored TPM (1.52; ) in comparison to all other AEDs Withdrawal rate was higher with OXC (OR 1.60; ) and TPM (OR 1.68; ), and lower with GBP (OR 0.65; ) and LEV(OR 0.62; ). Conclusions The differences are too small to allow a conclusion about which new AED(s) has superior effectiveness. The process of pharmacologic clinical decision making in refractory partial epilepsy probably depends more on other aspects.

9 SEIZURE FREEDOM IN ADJUNCTIVE TRIALS AED Dose Seizure free GBP % LTG % TPM % OXZ % LEV % ZNS % PGB % Adapted from Gazzola et al, Epilepsia 2007.

10 EXAMPLE: PGB vs LTG Kwan P et al. Efficacy and safety of PGB versus LTG in patients with newly diagnosed partial seizures. The Lancet Neurology 2011; 10: Methods Phase 3, double-blind, randomised, non-inferiority study compared the efficacy and tolerability of PGB and LTG monotherapy in patients with newly diagnosed partial seizures at 105 centres in Europe and Asia. Patients titrated to either 75 mg PGB or 50 mg LTG bid during escalation phase, followed by a 52-week assessment phase (max dose 600 mg and 500 mg). Findings Patients seizure-free for 6 months PGB 52% vs LTG 68%; (difference in %, 0 16, 95% CI 0 24 to 0 09). The incidence of adverse events was similar Conclusion: Difference in efficacy?

11 SANAD trial: first-line treatment (Marson et al 2007, Loescher & Schmidt 2011)

12 Systematic review and meta-analysis of the the placebo-corrected net efficacy of adjunctive treatment with modern AEDs for refractory epilepsy. 55 publications of 54 studies in 11,106 adults and children with refractory epilepsy. Overall weighted pooled-risk difference in favor of AEDs over placebo: 6% for seizure-freedom [95% CI 4-8, p<0.001] 21% for 50% seizure reduction (95% CI 19-24, p<0.001). The placebo-corrected efficacy of adjunctive treatment with modern AEDs is disappointingly small...

13 NEWLY DIAGNOSED EPILEPSY Response rates (%) in an expanding cohort Recruitment N One AED Multiple Total Kwan P, Brodie MJ. N Engl J Med 2000; 342: Mohanraj R, Brodie MJ. Eur J Neurol 2006; 13: Brodie MJ et al. Neurology, in press 13

14 ADVERSE EVENTS Acute dose-related: non-differentiating Common, benign, predictable Sedation, dizziness Idiosyncratic Rare, serious, unpredictable Skin, liver, bone marrow Unique to particular drugs: differentiating Vary by drug Reversibility varies

15 ADVERSE EVENTS Unique or differentiating EZG: urinary retention GBP: weight gain LCM:? LEV: behavior or psychiatric changes LTG: rash OXC: hyponatremia PGB: weight gain TGB:? TPM: cognition, weight loss, kidney stones ZNS: weight loss, kidney stones

16 EFFECTIVENESS A balance Combines efficacy and tolerability

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18 LTG ZNS OXC LEV TPM

19 RETENTION RATES 1-year Meta-ana Zaccara et al year 417 age >55 Arif et al year 249 with LD Simister et al year 1066 epil ctr Bootsma year 479 epil ctr Chung et al 2007 LEV CBZ 48 VPA 65 PHT 59 GBP LTG TPM TGB 24 OXC ZNS 63 60

20 RETENTION RATES 3-year 222 epil ctr Peltola et al year 1066 epil ctr Bootsma et al year 194 children Mills et al year 105 epil ctr Brandt et al year 593 elderly Rowan VA 428 LEV 46 CLB 51 GBP LTG TPM TGB 38 CBZ 35 PGB 40

21 LONGER TERM RETENTION RATES N 1 year 3 year 5 year Reason: lack of efficacy Reason: adverse events LTG % 29% 12% 34% 22% TPM % 30% 28% 19% 40% GBP % <10% 2% 39% 37% LEV % 37% 32% 18% 16% Lhatoo et al Epilepsia 2000;41: ; Krakow et al, Neurology 2001; 56:

22 OLD vs NEW Saetre E et al. An international multicenter randomized doubleblind controlled trial of lamotrigine and sustained-release carbamazepine in the treatment of newly diagnosed epilepsy in the elderly. Epilepsia 2007;48: METHODS Patients aged 65 years or older Randomized to receive LTG (n=93) or CBZ (n=92) Trial duration 40 weeks and included a 4-week dose escalation followed by a maintenance phase during which dosages could be adjusted according to response. RESULTS 40-week retention was 73% for LTG vs. 67% for CBZ (NS) Time to withdrawal (any cause): no difference (p=0.34) Seizure-freedom (last 20 weeks): 52% vs. 57% (NS) Adverse events leading to withdrawal: 14% vs. 25% (NS) CONCLUSION: LTG and CBZ had comparable effectiveness

23 Cumulative % of subjects continuously seizure-free and remaining in the study LEV vs CBZ-CR Time to discontinuation over first year of treatment (ITT population) LEV (N=285) CBZ-CR (N=291) Days Brodie MJ et al. Neurology 2007; 68: 402-8

24 LEV vs CBZ-CR One year seizure freedom (%) by dose level (per protocol population) % 89% 56.6% 58.4% % 10% 4% 1% 1g 2g 3g 400mg 800mg 1200mg Daily LEV dose Daily CBZ-CR dose Brodie MJ et al. Neurology 2007; 68: 402-8

25 SPECIAL EFFICACY FACTOR DANGER! Generalized Partial (Idiopathic) Childhood absence Benign focal Genetic Juvenile myoclonic epilepsy of Adult-onset IGE childhood Others Symptomatic West syndrome Temporal lobe (structural) Lennox-Gastaut syndrome Frontal lobe (metabolic) Others Others (unknown)

26 BROAD-SPECTRUM AEDs Yes VPA PB, Bzd TPM* LEV* LTG* ZNS? No PHT CBZ GBP OXC TGB PGB Unknown LCM EZG Biton V et al. A randomized, placebo-controlled study of TPM Neurology 1999;52: Biton V et al. Double-blind, placebo-controlled study of LTG Neurology 2005;65: Berkovic SF et al. Placebo-controlled study of LEV Neurology 2007;69:

27 AED PHT&CBZ VGB Mechanisms of action Na + Channel Blockade X Ca ++ Channel Blockade Glutamate Receptor Antagonism GABA Potentiation VPA X X X FBM X X X X GBP LTG X X X X X Carbonic Anhydrase Inhibition TPM X X X X X TGB OXC X X ZNS X X X PGB X X LEV: Synaptic vesicle protein 2A LCM: Na channel slow inactivation EZG: K channel Adapted from Kwan et al, 2001, Upton 1994, Schachter 1995, McDonald & Kelley 1995, Meldrum 1996, Coulter 1997, White 1999

28 DRUG INTERACTIONS Mean number of prescription medications in the elderly population is 6.7 (range 0-15) AEDs are among the leading medications responsible for drug interactions Most drug interactions occur within CYP-450 enzyme system Co-administered medications Psychotropics Dementia Rx Asthma Rx Anticoagulants/antiplatelets Antihypertensives Lipid-lowering agents Antidiabetic agents Ramsay RE, et al. Neurology. 2004;62(5 suppl 2):S24-S29.

29 EFFECTS OF OLDER AEDS ON SERUM CONCENTRATIONS OF NEWER AEDS* Adapted from French JA, et al. Epilepsia. 2000;41(suppl 8):S30-S36.

30 EFFECTS OF NEWER AEDS ON SERUM CONCENTRATIONS OF OLDER AEDS Adapted from French JA, et al. Epilepsia. 2000;41(suppl 8):S30-S36.

31 DRUG INTERACTIONS A group difference Older AEDs vs. newer AEDs No significant differences among the newer AEDs

32 Pregnancy & birth defects Mølgaard-Nielsen D, Hviid A. Newer-generation antiepileptic drugs and the risk of major birth defects. JAMA 2011;305(19): DESIGN: Population-based cohort study of 837,795 live-born infants in Denmark from 1996 to RESULTS: 1532 infants exposed to LTG, OXC, TPM, GBP, or LEV in first trimester 49 diagnosed with a major birth defect compared with 19,911 of the 836,263 not exposed to an AED 3.2% vs 2.4%; adjusted POR [APOR], 0.99; 95% CI ). LTG 38/1019 = 3.7% OXC 11/393 = 2.8% TPM 5/108 = 4.6% GBP 1/59 = 1.7% LEV 0/58 = 0 % CONCLUSION: First-trimester exposure was not associated with an increased risk of major birth defects.

33 Cognitive function after fetal drug exposure Meador K et al. N Engl J Med 2009; 360:

34 USE OUTSIDE OF EPILEPSY FDA approved (PI) Not FDA approved Reference CBZ Pain (Trigeminal neuroalgia) Bipolar (Too many) GBP LCM LEV LTG Pain (Post-herpetic neuralgia) RLS Bipolar Other pain (Too many) OXC None Bipolar (Kakkar et al, Eur Psychiatr 2009) PGB Pain (Diabetic neuropathy, Postherpetic neuralgia, fibromyalgia ) Anxiety (Boschen. Can J Psychiatry 2011) PRM Essential tremor (Zesiewicz et al, Neurology 2011) TPM Migraine Obesity (Kramer et al. Obes Rev 2011) Essential tremor (Zesiewicz et al, Neurology 2011) VPA Migraine, bipolar ZNS Obesity (Wellmer et al, Acta Neurol Scand 2009)

35 OFF-LABEL USE (monotherapy, age) Good medical practice and the best interests of the patient require that physicians use legally available drugs and devices according to their best knowledge and judgment. If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product's use and effects.

36 COMPLIANCE RATES AND DOSING SCHEDULE Cramer JA et al. How often is medication taken as prescribed? A novel assessment technique. JAMA 1989;261(22): Medication Event Monitor Systems Standard pill bottles with micro-processors in the cap to record every bottle opening as a presumptive dose. qd 87% bid 81% tid 71% qid 39%

37 FORMULATIONS Extended-release (XR, ER, SR etc.) VPA, CBZ, LEV, LTG A relatively small benefit Worth the cost? IV availability LEV, LCM A significant benefit, but Use in status is off-label

38 TITRATION Time to effective dose Only 2 outliers LTG TPM Escalation schedule by weekly 25 mg increments About 7 weeks to reach 100 mg bid

39 COST & GENERICS Pros and cons of generics Generic availability All but PGB, LCM Not all XR preparations

40 SO DO THEY DIFFERENTIATE? NO YES MAYBE Efficacy Type I side effects Pregnancy Cost FDA indications Monotherapy Pediatrics/age Tolerability & AE Broad spectrum Drug-drug interactions Treatment of comorbidities Dosing Titration

41 NEWER AEDS AS A GROUP (VS. OLD) Same In clinical trials, 25-40% in seizure frequency: comparable efficacy Still have the typical, common, benign, predictable and dose related side effects Better Better side effect profile Positive side-effects Less drug-interactions

42 POSITION STATEMENT ON THE COVERAGE OF ANTICONVULSANT DRUGS FOR THE TREATMENT OF EPILEPSY (NOV 2006) The AAN supports the use of newergeneration anticonvulsant drugs in the treatment of epilepsy. Newer generation anticonvulsant drugs generally result in fewer and less-severe side-effects, although they may be more expensive...

43 Glaser T, et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med 2010;362(9): METHODS Double-blind, randomized, controlled clinical trial, to compare efficacy, tolerability, and neuropsychological effects of ETX, VPA, and LTG in children with newly diagnosed childhood absence epilepsy. Drug doses were increased until seizure freedom, the maximal allowable or tolerable dose was reached, or a criterion indicating treatment failure was met. RESULTS The 453 children who were randomly assigned to treatment with ETX (156), LTG (149), or VPA (148). Freedom-from-failure rates similar for ETX (53%) and VPA (58%) Lower for LTG (29%). No significant differences among the three drugs with regard to discontinuation because of adverse events. Attentional dysfunction more common with VPA (49%) than with ETX (33%) CONCLUSIONS ETX and VPA are more effective than LTG in the treatment of childhood absence epilepsy. ETX is associated with fewer adverse attentional effects.

44 COMPARING THE COMPARISON Fibromyalgia: duloxetine vs. milnacipran vs. pregabalin CIDP: IgIV vs. steroids vs plasmapheresis RLS: gabapentin vs. ropinorole vs. pramipexole Antidepressants: MAOI, TCA, SSRI, SNRI

45 Relative benefit of response comparing SSRIs, SSNRIs, SNRIs, and other second-generation antidepressant... Gartlehner G et al. Ann Intern Med 2008;149: by American College of Physicians

46 Random effects model of clinical response in randomised controlled trials of mood stabilising medication Van Lieshout R J, MacQueen G M BJP 2010;196: by The Royal College of Psychiatrists

47 NEUROSTIMULATION EFFICACY VNS (Handforth et al. Neurology 1998;51:48-55) Seizure reduction 28% vs. 15% DBS (Fischer et al. Epilepsia 2010;51: ) Seizure reduction 30-40% vs. 14% RNS (Morrell et al. Neurology 2011;77: ) Seizure reduction 38% vs 17%

48 THE MYSTERIOUS AED

49 NOT AN AED Wiebe et al. N Engl J Med 2001;345(5):311-8.

50 CONCLUSIONS No significant difference in efficacy Some difference in tolerability Group difference (old vs. new) Main differentiating points among individual AEDs Drug-specific side effects Positive effects on comorbidities Broad-spectrum